pci-32765 and Brain-Neoplasms

Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.

Topics: Adenine; Amino Acid Substitution; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Mutation, Missense; Myeloid Differentiation Factor 88; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Drug Delivery Systems; Glioblastoma; Mice; Pericytes; Piperidines; Pyrazoles; Pyrimidines; Tumor Microenvironment; Xenograft Model Antitumor Assays

Richter's syndrome (RS) of the central nervous system (CNS) is known to have an extremely poor prognosis. Ibrutinib has been reported to have some activity in patients with RS, despite its poor prognosis. Although ibrutinib crosses the blood-brain barrier, its efficacy in RS patients with CNS involvement remains unknown. Here, we report a case of RS isolated in the CNS that was confirmed to be clonally related to chronic lymphocytic leukemia (CLL) by immunoglobulin heavy chain gene analysis. Although the median survival of patients with RS clonally related to CLL was significantly shorter than that of patients with RS clonally unrelated to CLL, the patient received ibrutinib monotherapy without experiencing any significant adverse events, and the disease remained stable with ibrutinib until 6 weeks later. Following whole-brain radiation therapy (40 Gy in 20 fractions) with dexamethasone, the patient has survived for five months after diagnosis. Thus, ibrutinib may be a safe and effective therapeutic option for patients with RS and CNS involvement.

Topics: Brain Neoplasms; Central Nervous System; Cranial Irradiation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Animals; Aspergillosis; Brain Neoplasms; CD79 Antigens; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gene Knockout Techniques; Humans; Lymphoma; Male; Mice; Mice, Knockout; Middle Aged; Myeloid Differentiation Factor 88; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed.. In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo.. Our data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells.. Taken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Neoplasm Transplantation; NF-kappa B; Piperidines; Prognosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Survival Analysis; Transcriptional Activation; Up-Regulation

The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Capillary Permeability; Glioma; Humans; Mice; Neoplastic Stem Cells; Pericytes; Piperidines; Prognosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Survival Analysis; Tight Junctions; Treatment Outcome

We describe a 71-year-old-patient receiving antiplatelet therapy and being attended by emergency medical services for psychomotor retardation and gait disturbance. An emergency computed tomographic scan showed a bilateral subacute hematoma. The patient reported a fall 2 weeks earlier. We performed bilateral drills and saw a solid mass that was biopsied. The patient had a history of mantle cell lymphoma (MCL) in complete remission (results of bone marrow biopsy and whole-body positron emission tomography-computed tomography scans were normal 6 months earlier). We diagnosed an intracranial MCL by immunohistochemistry, flow cytometry, and fluorescence in situ hybridization. We performed magnetic resonance imaging. The results of a new bone marrow biopsy were positive for recurrence of MCL. MCL constitutes approximately 5%-6% of non-Hodgkin lymphoma. The incidence of central nervous system (CNS) involvement between MCLs is 4.1%. After a review of the literatures we found small series comprising 3-5 cases and a multicenter study with 57 cases. Until now, the median survival was 3.7 months. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, has demonstrated efficacy and CNS penetration in relapsed or refractory MCL with rapid and complete response even after 1 year of follow-up. Our patient received ibrutinib and had a complete response at 3 months, which was maintained to the present (6 months). After a review of the literature, we found different pathologies that can mimic subdural hematomas. However, this is the first report of a lymphoma with CNS involvement mimicking bilateral subdural hematomas. This report contributes to the knowledge of lymphomas with CNS involvement. Its strange radiographic appearance and histologic type make it unique.

Topics: Adenine; Aged; Antineoplastic Agents; Brain Neoplasms; Diagnosis, Differential; Hematoma, Subdural; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Brain Neoplasms; Cell Line, Tumor; Female; Glioma; Humans; Male; Mice; Middle Aged; Neoplastic Stem Cells; Phenotype; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines